Stroke is the third leading cause of death and the number one cause of disability in the United States, and cardiovascular disease totals close to $200 billion annually. Further, subclinical vascular damage has been associated with a greater risk of clinical stroke, disability, and cognitive decline. Unfortunately, known modifiable risk factors for vascular disease do not completely explain overall risk for stroke and these other vascular outcomes, mandating the identification of novel mechanisms and biomarkers of disease. Increased levels of serum fibroblast growth factor 23 (FGF23) and phosphate have emerged as novel risk factors for cardiovascular disease (CVD) and mortality. We were the first to demonstrate that increased FGF23 levels at the initiation of dialysis are independently associated with an increased risk of mortality, and these results have now been validated in the general population. However, few studies have examined these markers in relation to stroke risk. Further, it is not understood if FGF23 and disordered phosphorus metabolism increase the risk of vascular events through small or large vessel damage and whether they are associated with subclinical cerebrovascular damage - a potent risk factor for clinical stroke and cognitive decline. In our population-based multi-ethnic Northern Manhattan Study (NOMAS) we have found subclinical infarction and cerebral small vessel disease to be prevalent and associated with poor cognitive function. Increased FGF23 and phosphate can be lowered, so demonstrating that these factors are independently associated with adverse neurological outcomes could have important therapeutic potential. We will test the hypothesis that elevated FGF23 and serum phosphate are independent risk factors for incident stroke, subclinical vascular damage, and cognitive decline. We further hypothesize that higher FGF23 levels are the key marker of phosphorus-related CVD risk. We will measure FGF23 and phosphate in the existing NOMAS cohort of 3,248 participants, initially stroke-free and now followed for an average of 10 years for carefully adjudicated vascular events, as well as in 1,290 participants of the subsample that underwent quantitative brain MRI and carotid ultrasound to measure subclinical vascular damage, and global as well as detailed neuropsychological assessments. We propose the following three aims: 1) perform the largest prospective cohort study to date to evaluate baseline FGF23 and serum phosphate levels as risk factors for incident stroke, independent of conventional CVD risk factors and kidney disease; 2) evaluate FGF23 and serum phosphate as novel risk factors for subclinical small and large vessel injury, in a subcohort who underwent brain MRI to measure white matter damage volumes and subclinical infarction, as well as quantitative carotid ultrasound measures of intima media thickness, distensibility, and carotid plaque thickness; and 3) to evaluate FGF23 and serum phosphate as predictors of cognitive decline. We anticipate that the results of this study, in concert with our ongoing projects on FGF23 in more advanced CKD, will rapidly set the stage for randomized controlled trials. PUBLIC HEALTH RELEVANCE: Elevated fibroblast growth factor 23 and serum phosphate are novel risk factors for cardiovascular disease and mortality, but their association with cerebrovascular damage is not clear. This study takes advantage of an ongoing population-based cohort study that includes Hispanic, black, and white people living in the same community, to examine elevated serum FGF23 and phosphate and the risk for stroke, subclinical small and large vessel injury, and cognitive decline. Elevated serum phosphate is modifiable and the results of this study have therapeutic potential that can be tested in randomized clinical trials.